The present invention relates to the diagnosis of tauopathies. The present invention provides a new method for the detection and/or differential diagnosis of tauopathies. The present invention also provides a phospho-peptide that can be used for standardization in a method of the invention.
Several forms of dementia, the so-called tauopathies (Goedert et al., 1998), have been associated with the same pathophysiological mechanism, the involvement of the structural protein tau. The microtubule-associated protein tau is for example a major protein component of paired helical filaments (PHF) and neurofibrillar tangles (NFT), associated with Alzheimer""s disease (Brion et al., 1985; Delacourte and Defossez, 1986; Grundke-Iqbal et al., 1986; Kosik et al., 1986; Wood et al., 1986; Kondo et al., 1988). Tau protein exists in different isoforms, of which 4 to 6 are found in adult brain but only 1 isoform is detected in fetal brain. The diversity of the isoforms is generated from a single gene on human chromosome 17 by alternative mRNA splicing (Himmler, 1989; Goedert et al., 1989; Andreadis et al., 1992). The most striking feature of tau protein, as deduced from molecular cloning, is a stretch of 31 or 32 amino acids, occurring in the carboxy-terminal part of the molecule, which can be repeated either 3 or 4 times. Additional diversity is generated through 29 or 58 amino acid-long insertions in the NH2-terminal part of tau molecules (Goedert et al., 1989). In vivo tau promotes microtubule assembly and stability in the axonal compartment of neurons by interactions involving its microtubule binding domain which is localized in the repeat region of tau (255-381) (Lewis et al., 1988). In normal circumstances adult brain contains 2-3 mole phosphate per mole of tau (Selden and Pollard, 1983; Ksiezak-Reding et al., 1992). Phosphorylation of different sites in normal tau as studied in rat and humans is dependent on the developmental state (Lee et al., 1991; Bramblett et al., 1993; Goedert et al., 1993). Tau variants of 60, 64 and 68 kDa arising as a consequence of phosphorylation have been detected in brain areas showing neurofibrillary tangles (Delacourte et al., 1990; Goedert et al., 1992; Flament et al., 1990, Greenberg and Davies, 1990). These brains contain 6-8 mole phosphate per mole tau (Ksiezak-Reding et al., 1992). In tau isolated from PHF (PHF-tau), phosphorylation occurs at several positions (Iqbal et al., 1989; Lee et al., 1991; Hasegawa et al., 1992; Hanger et al., 1998; Buee et al., 1999).
Alzheimer""s disease (AD) is the most common type of primary degenerative dementia associated with a tau pathology, having a prevalence of 42-75% (Brun, 1993; Gustafson, 1993; Ebly et al., 1994). Frontotemporal dementia (FTD) is a clinical condition in which pathologically Pick""s disease, Frontotemporal dementia with Parkinsonism linked to chromosome 17, sporadic FTD and motor neuron disease are present. According to a small study by Mann et al. (2000), 16 of the 37 cases with FTD could be classified as tauopathy based on tau-immunohistochemistry. Filamentous tau pathology i.e. neurofibrillary tangles (NFT), are consistently found in AD (Tomlinson and Corsellis, 1984) but may also be found in FTD (Spillantini and Goedert, 1998). Pathological tau proteins are found both in AD and FTD (Vermersch et al., 1995; Delacourte et al., 1996), however studies on brain tissue have suggested that the tau pathology differs between AD and FTD, possibly being related to the degree of phosphorylation (Delacourte et al., 1996). Other forms of dementia associated with a tau pathology include Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD) and Subacute sclerosing panencephalitis. The role of hyperphosphorylation in the pathology of these tauopathies is at present not well understood. In addition, various difficulties have been encountered in the accurate determination of the degree of phosphorylation of specific phospho-sites concentrated in the proline region. Because of these difficulties, an accurate method for the specific detection of these tauopathies is still lacking.
The present invention relates to a method for the diagnosis of a tauopathy in an individual, said method involving:
determining the ratio of phospho-tau (181)/total tau in said individual;
inferring that said individual is suffering a tauopathy by comparing the obtained ratio of phospho-tau (181)/total tau in said individual with the ratio of phospho-tau (181)/total tau in control individuals, whereby an altered ratio of phospho-tau (181)/total tau compared to said ratio in control individuals being an indication of tauopathy.
The present invention also relates to a method for the differential diagnosis of a tauopathy versus a non-tauopathy in an individual, said method involving:
determining the ratio of phospho-tau (181)/total tau in said individual;
inferring that said individual is suffering a tauopathy by comparing the obtained ratio of phospho-tau (181)/total tau in said individual with the ratio of phospho-tau (181)/total tau in individuals suffering a non-tauopathy or with the phospho-tau (181)/total tau ratio in control individuals, whereby an altered ratio of phospho-tau (181)/total tau compared to said ratio in individuals suffering a non-tauopathy or in control individuals being an indication of tauopathy.
It is an aim of the present invention to provide a method for the diagnosis of a tauopathy in an individual.
It is another aim of the present invention to provide a method for the diagnosis of Alzheimer""s disease, Pick""s disease, sporadic Frontotemporal dementia and/or Frontotemporal dementia with Parkinsonism linked to chromosome 17 in an individual.
It is another aim of the present invention to provide a method for the differential diagnosis of a tauopathy versus a non-tauopathy.
It is another aim of the present invention to provide a method for the differential diagnosis of a tauopathy versus a non-tauopathy neurodegeneration.
It is another aim of the present invention to provide a method for the differential diagnosis of a tauopathy versus vascular dementia, Creutzfeldt Jacob Disease, stroke and/or neurotoxicity in patients with leukemia.
It is another aim of the present invention to provide a method for the differential diagnosis of Alzheimer""s disease, Pick""s disease, sporadic Frontotemporal dementia and/or Frontotemporal dementia with Parkinsonism linked to chromosome 17 versus vascular dementia, Creutzfeldt Jacob Disease, stroke and/neurotoxicity in patients with leukemia.
It is another aim of the present invention to provide an in vitro method as described above.
It is another aim of the present invention to provide a phospho-peptide for use in standardization.
It is another aim of the present invention to provide a phospho-peptide for use in standardization in a method to detect phospho-tau (181).
It is another aim of the present invention to provide a phospho-peptide for use in standardization in a method as described above.
It is another aim of the present invention to provide a diagnostic kit for use in a method as described above.
It is another aim of the present invention to provide a peptide, a method and/or a diagnostic kit for the testing or screening of drugs, for therapeutic monitoring and/or for the determination of the effectiveness of a certain treatment for a tauopathy.